Patent application WO 95/00497 published Jan. 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993).
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Compounds useful in the claimed methods are represented by Formula 1.0: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A represents N or N-oxide;
X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines;
R1 is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, acylamino or alkoxy;
R2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, xe2x80x94OCF3, hydroxy, amino or acylamino;
R3 is hydrogen, bromo, chloro, alkoxy, xe2x80x94OCF3 or hydroxy;
R4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy;
provided that at least one of R2 or R3 or R4 is alkyl or alkoxy and provided that at least two of R1, R2, R3 or R4 are substituents other than hydrogen;
Q is hydrogen when there is a single bond to carbon atom 11, or Q is hydrogen or hydroxy when there is a single bond to carbon 11 and X is CH, or Q is not a substituent when there is a double bond to carbon 11;
R5, R6, R7 and R8 independently represent hydrogen, alkyl or xe2x80x94CONHR50 wherein R50 can be any of the values represented for R, below; 
Z is xe2x95x90O or xe2x95x90S; and
R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.
Preferably in compound (1.0), there is a single bond or a double bond at carbon atom 11; X is N, CH or C; R1 is H, halo, alkyl, cycloalkyl or alkenyl; R2 is H, halo, alkoxy, or alkyl; R3 is H, halo, alkoxy, hydroxy or alkyl; and R4 is H, halo or alkyl; R5, R6, R7 and R8 are hydrogen; Y is xe2x80x94SO2CH3 or xe2x80x94COR wherein R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl, preferably piperidinyl-methyl. When R1 is other than hydrogen, preferably the halo moiety is bromo, the alkyl is methyl or ethyl, the cycloalkyl is cyclopropyl or the alkenyl is vinyl. When R2 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R3 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R4 is other than hydrogen, preferably the halo moiety is chloro or the alkyl is methyl. Preferred title compounds include those of Examples 1-10 and 14-37, preferably those of Examples 1, 2, 3, 6, 7, 8, 10, 16, 18, 19, 21, 22, 24, 26, 27, 29, 33, 34, 35, 36 and 37, more preferably those of Examples 3, 21, 22, 24 and 33, disclosed hereinafter.
In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention is directed toward a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein. Without wishing to be bound by theory, it is believed that these compounds may function either through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer, or through inhibition of ras farnesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells.
The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, the types of cells that may be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. Also, the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase. The inhibition may be of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene. Alternatively, compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, prostate carcinoma and breast carcinoma and epidermal carcinoma.
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition being accomplished by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited by the N-substituted urea compounds (1.0).
In another embodiment, the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and the farnesylation of the oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
As used herein, the following terms are used as defined below unless otherwise indicated:
M+xe2x80x94represents the molecular ion of the molecule in the mass spectrum;
MH+xe2x80x94represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
Buxe2x80x94represents butyl;
Etxe2x80x94represents ethyl;
Mexe2x80x94represents methyl;
Phxe2x80x94represents phenyl;
benzotriazol-1-yloxy represents 
1-methyl-tetrazol-5-ylthio represents 
alkylxe2x80x94(including the alkyl portions of alkoxy, alkylamino and dialkylamino)xe2x80x94represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo (i.e. trifluoromethyl), alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10 (i.e. hydroxymethyl, hydroxyethyl), xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 can independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
acylaminoxe2x80x94refers to the moiety xe2x80x94CONR10R12 wherein R10 and R12 are defined hereinbefore;
alkoxyxe2x80x94an alkyl moiety of one to 20 carbon atoms covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aryl (including the aryl portion of aralkyl)xe2x80x94represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is phenyl), wherein said aryl group optionally can be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aralkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10, or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
aryloxyxe2x80x94represents an aryl group, as defined above, wherein said aryl group is covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy, wherein said aryl group optionally can be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryloxy group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkylxe2x80x94represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; wherein said cycloalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
cycloalkylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more cycloalkyl groups; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
haloxe2x80x94represents fluoro, chloro, bromo and iodo;
heteroalkylxe2x80x94represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94; wherein any of the available substitutable carbon and nitrogen atoms in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heteroarylxe2x80x94represents cyclic groups having at least one heteroatom selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 2 to 14 carbon atoms,wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R12 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove.
Representative heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: 
heteroarylalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove;
heterocycloalkylxe2x80x94represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94Nxe2x80x94, wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein any of the available substitutable carbon and nitrogen atoms in the ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove. Representative heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, 
or wherein R10 is defined hereinbefore and t is 0, 1 or 2.
heterocycloalkalkylxe2x80x94represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, xe2x80x94CF3, oxy (xe2x95x90O), aryloxy, xe2x80x94OR10, xe2x80x94OCF3, heterocycloalkyl, heteroaryl, xe2x80x94NR10R12, xe2x80x94NHSO2R10, xe2x80x94SO2NH2, xe2x80x94SO2NHR10, xe2x80x94SO2R10, xe2x80x94SOR10, xe2x80x94SR10, xe2x80x94NHSO2, xe2x80x94NO2, xe2x80x94CONR10R12, xe2x80x94NR12COR10, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R10 or xe2x80x94COOR10, wherein R10 and R12 are as defined hereinabove.
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc orAcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); ethyl chloroformate (ClCO2Et); lithium di-isopropylamide (LDA) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl or DEC).
Reference to the position of the substituents R1, R2, R3 and R4 is based on the numbered ring structure: 
Certain compounds of the invention may exist in different steroisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers). The invention contemplates all such steroisomers both in pure form and in mixture, including racemic mixtures. For example, the carbon atom at the C-11 position can be in the S or R steroconfiguration.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purpopses of the invention.
Compounds of the present invention can be prepared according to the following Schemes I, II or III wherein 
A, R1, R2, R3, R4, R5, R6, R7, R8, Y, the solid and dotted lines are as defined hereinbefore.
In Scheme I, compound 1.0 wherein 
and Zxe2x95x90O wherein R is defined hereinbefore, can be prepared by acylating compound (11, 11.3), (19, 19.3) or (20, 20.3) with a carboxylic acid of the formula RCOOH (30.0) wherein R is defined hereinbefore, in an aprotic solvent, at temperatures ranging from about 0xc2x0 to 20xc2x0 C., using about 1 to 2 moles of carboxylic acid (30.0) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3).
Alternatively, compound 1.0 wherein Yxe2x95x90SO2R, can be prepared by reacting compound (11, 11.3), (19, 19.3) or (20, 20.3) with a sulfonyl chloride of the formula RSO2Cl (20.7) wherein R is as defined before, in a solvent such a pyridine and a base such as 4-dimethylaminopyridine or triethylamine, using 1 to 3 moles of sulfonyl chloride (20.7) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). The amount of base can range from catalytic to about 1.5 moles per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3).
The compounds of formula (1.0) wherein A is Nxe2x80x94O (i.e. the N-oxide), can be prepared by treating compound (1.0) wherein A is N with metachloroperbenzoic acid (MCPBA) in an aprotic solvent such as methylene chloride at temperatures ranging from about 0xc2x0 to 25xc2x0 C., using 1 to 2 equivalents of MCPBA per mole of compound (1.0).
The sulfur-containing compounds of formula (1.0) wherein Zxe2x95x90S, can be treating compounds (1.0) wherein Zxe2x95x90O with a sulfurating agent such as Lawesson""s Reagent in a suitable aprotic solvent such as toluene at about 100xc2x0 C. to give the thioamide (1.0). Alternative sulfurating reagents include bis-(1,5-cyclooctanediarylboryl)sulfide in hexane at xe2x88x9278xc2x0 C.; or phosphorous pentasulfide (P2S5, also of the formula P4S10) in toluene at reflux temperatures, or in THF using ultrasound at 40xc2x0 C.; or bis-(9-Borabicyclo[3.3.1]nonane)sulfide ((9-BBN)2S) in heptane at reflux temperatures.
Compounds of formula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic media. Alternatively, compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation.
Compounds of formula 1.0, 1.0a and 1.0b in Scheme I, wherein X is CH or N may be racemates. These racemates can be resolved into their (+) and (xe2x88x92) enantiomers by HPLC procedures on Chiralpak columns (Daicel Chemical Ind.). Alternatively, (+)-Isomers of compounds of formula (19, 19.3, 20, 20.3) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of formula (19, 19.3, 20, 20.3), wherein X is C, the double bond is present and X3 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R3 is not H. Altematively, a racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C, the double bond is present and R3 is not H, is first reduced to the corresponding racemic compound of formula (19, 19.3, 20, 20.3) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.
Compounds of the present invention and preparative starting materials thereof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure.